Summary

• REMICADE has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include anaphylaxis, urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of REMICADE infusion.¹
• An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase 3 clinical studies, 18% of REMICADE-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients.¹
• Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of REMICADE infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of REMICADE. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms.¹
• Prior to infusion with REMICADE, premedication may be administered at the physician’s discretion. Premedication could include antihistamines (anti-H₁ +/- anti-H₂), acetaminophen and/or corticosteroids.¹
• Summaries of an open-label study², a case-control study³, a prospective review⁴, and retrospective reviews^5-12 which evaluated the incidence of infusion-related reactions in patients treated with REMICADE are provided below.

CLINICAL DATA: REMICADE CLINICAL TRIALS

Adult Patients

Clinical trials, conducted primarily in adult patients with RA, CD, ankylosing spondylitis (AS), psoriatic arthritis (PsA), plaque psoriasis, and ulcerative colitis (UC), have evaluated the safety and efficacy of REMICADE in 5707 REMICADE-treated patients and 1600 placebo-treated patients.¹³

• The majority of the data presented reflect both single and repeat-dosing regimens, including chronic maintenance therapy through as long as 102 weeks.¹³
• The average duration of follow-up for studies in RA, CD, AS, PsA, plaque psoriasis, and UC was 45.5 weeks for patients receiving REMICADE and 29.0 weeks for patients receiving placebo.¹³

Infusion-related reactions which have occurred in ≥1% of REMICADE-treated patients in all clinical studies are summarized in Table: Infusion-related Reactions Observed in ≥1% of Patients in REMICADE Clinical Trials.¹⁴

A randomized, multicenter, open-label study was conducted to assess the safety and efficacy of long-term maintenance therapy vs intermittent therapy with REMICADE in adults with moderate to severe psoriasis who were not receiving concomitant immunosuppressant therapy.¹⁵

• This was the long term extension of an initial 26-week, randomized, open-label study comparing the efficacy and safety of REMICADE vs methotrexate (MTX) in the treatment of adults with moderate to severe plaque psoriasis.
• A total of 441 patients who received REMICADE in the initial study and had achieved a ≥75% improvement in baseline Psoriasis Area and Severity Index (PASI) score were randomized to receive either maintenance (n=222) or intermittent reinduction (n=219) REMICADE treatment in this study extension.
  • Patients in the maintenance treatment arm received 5 mg/kg REMICADE infusions every 8 weeks as a continuation of their treatment from the previous study.
  • Patients in the intermittent arm received no REMICADE treatment until their PASI score was reduced by more than 50% from baseline. At that time, patients received a 5 mg/kg REMICADE infusion and then subsequent infusions at weeks 2, 6, and 14 as a reinduction regimen until response (≥75% improvement in original PASI score from the previous trial) was reached (up to 4 infusions). These intermittent treatment cycles were repeated whenever the PASI score decreased by 50%.

Infusion-related reactions occurred in 52 (3%) of the total 1672 REMICADE infusions during this study.¹⁵

• A greater number of infusion-related reactions, both nonserious and serious, occurred in infusions in the intermittent REMICADE treatment arm compared to the maintenance treatment arm (5% vs 2%).
• Twenty-nine (13%) patients in the intermittent arm experienced infusion-related reactions, of which 8 (4%) were considered serious compared to 16 (7%) total reactions in the maintenance arm and 1 (<1%) serious.
  • For the 8 serious infusion-related reactions that occurred in the intermittent treatment arm, the range of the drug free interval was between 35-224 days and the majority occurred during the second infusion at week 2.
  • Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension.
  • In all cases, REMICADE treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
• The study was discontinued prematurely due to an imbalance observed in the number of reported serious infusion-related reactions between the maintenance and intermittent reinduction arms.

Pediatric Patients

• In a prospective open-label clinical study evaluating the efficacy and safety of REMICADE in 112 pediatric patients 6 years of age and older with moderately to severely active CD, 18% of patients experienced 1 or more infusion reactions. There were no serious infusion reactions, and 2 patients had nonserious anaphylactoid reactions.¹
• During the open-label phase 3 clinical study evaluating the efficacy and safety of REMICADE in 60 pediatric patients aged 6-17 years old with moderately to severely active UC, 13% (8/60) of treated patients experienced 1 or more infusion reactions. No serious infusion reactions were reported.¹

CLINICAL DATA: Published Literature

Kobayashi et al (2021)² conducted an open-label, multicenter, randomized controlled trial in adult patients with ulcerative colitis in remission (for ≥6 months after enrollment) to compare outcomes between patients who continued REMICADE and those who discontinued REMICADE.

• Patients who continued treatment received REMICADE 5 mg/kg intravenous (IV) every 8 weeks. Dose escalation or shorter intervals were not allowed.
• Patients who discontinued treatment stopped REMICADE after randomization.
  • Patients who relapsed were given hydrocortisone 100 mg IV or methylprednisolone 20-40 mg IV as premedication followed by REMICADE 5 mg/kg IV at weeks 0, 2 and 6 for re-treatment.
    • Efficacy was evaluated at week 8 after re-treatment.
• A total of 95 patients were randomly assigned to either the REMICADE-continued group (n=48) or the REMICADE-discontinued group (n=47).
• Among the 48 patients who continued treatment with REMICADE, one patient experienced an infusion reaction.
• Retreatment with REMICADE was implemented in 57% (12/21) of patients in the REMICADE-discontinuation group who relapsed.
  • Of these 12 patients, no infusion-related reactions occurred during the observation period after the reintroduction of REMICADE within 8 weeks.

Van Wassenaer et al (2019)³ reported the results from a case-control study that evaluated the influence of steroid premedication on the incidence of infusion reactions in pediatric (<18 years old) patients with inflammatory bowel disease treated with REMICADE.

• A total of 226 patients were included in this study (premedicated group, n=91; non-premedicated group, n=135).
• Infusion reactions were reported in 14.3% of patients (13/91) in the premedicated group and in 17% of patients (23/135) in the non-premedicated group.
  • In the premedicated group, 3 infusion reactions were classified as severe (dyspnea and angioedema), and 3 infusion reactions were classified as grade 4.
  • In the non-premedicated group, there were no severe infusion reactions and 1 infusion reaction was classified as grade 4.
• In the non-premedicated group, 9 patients who had experienced infusion reactions eventually received premedication. Of these 9 patients, 3 continued experiencing infusion reactions, 4 did not, and there was limited information on the remaining 2 patients.
• Other infusion reactions reported include headache (n=7); nausea and/or vomiting (n=6); rash (n=6); chest pain (n=4); dizziness (n=2); and chills, pruritus, edema, and temperature rise (n=1, each).
• On average, the first infusion reaction (n=36) occurred at the 6^th infusion (standard deviation [SD], 5.72; range, 1-24), the second (n=11) occurred at the 7^th infusion (SD, 5.52; range, 2-18), and the third (n=2) occurred at the 6^th infusion (SD, 3.54; range, 3-8).
• When correcting for the use of co-medications, the odds ratio was 1.06 (95% CI, 0.49 to 2.27; P=0.89) for developing any infusion reaction and 0.90 (95% CI, 0.24 to 3.39; P=0.88) for developing a grade 3 or 4 infusion reaction in the premedicated group.

Choquette et al (2015)⁴ evaluated the incidence and management of infusion reactions to REMICADE in a multicenter, prospective, Canadian observational registry (RemiTRAC Infusion).

• A total of 1632 patients were enrolled from August 2005 to October 2012. There were 24,852 infusions recorded.
• Patients were treated for RA (40.1%), CD (18.8%), AS (17.5%), plaque psoriasis (9.4%), UC (6.7%), or PsA (5.5%).
• The mean number of REMICADE infusions administered per patient was 15.3.
• A total of 201 (12.3%) patients reported ≥1 infusion reaction.
• Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate (95%).
• Infusion reactions included: pruritus (19.9%), flushing (9.9%), dyspnea (6.2%), nausea (4.7%), urticaria (4.7%), headache (4.0%), hypertension (3.7%), rash (3.4%), chest discomfort (3.1%), chest pain (2.8%), dizziness (2.8%), back pain (2.5%), muscle spasms (2.5%), blood pressure increased (2.2%), generalized pruritus (2.2%), and other, with an incidence of <2% (25.5%).
• Multivariate analysis showed that premedication with antihistamines (2.49% vs 1.32% if not used, P<0.0001), number of previous infusion reactions (odds ratio [OR] 2.04 [95% confidence interval (CI), 1.78-2.34], P<0.0001), time in days since last infusion (OR 0.99 [95% CI, 0.99-1.00], P<0.0006), female sex (2.21% vs 1.49% for males, P<0.0001), and the use of corticosteroids at enrollment in patients with previous infusions with REMICADE (2.98% vs 1.20%, P<0.002) were significantly associated with an increased incidence of infusion reactions. The incidence of infusion reaction decreased with each passing year (OR 0.68 [95% CI, 0.63-0.73], P<0.0001).
• A propensity scores-adjusted effect analysis showed that premedication with antihistamines (OR 1.58, P=0.0007) and steroids (OR 1.50, P=0.0057) had a significantly higher rate of infusion reactions compared to no treatment. Steroids alone had no significant effect on infusion reactions (OR 1.00, P=0.9900); only when they were used with antihistamines did a risk of reaction increase compared with no pretreatment (OR 3.34, P<0.0001). Antihistamines alone significantly increased the risk of infusion reactions (OR 1.79, P=0.0129).

Checkley et al (2019)¹² conducted a retrospective chart review to evaluate the incidence of infusion reactions after administration of REMICADE and associated management approaches in adult patients with Crohn’s disease or ulcerative colitis (N=796).

• Clinical charts of patients who received REMICADE at home or via an ambulatory infusion suite from January 2014 to November 2016 were reviewed.
• Patients received a mean of 7 infusions during the study period and the mean REMICADE dose was 531 mg.
• A total of 109 infusion reactions were reported in 7.8% of patients (62/796).
  • Most infusion reactions were reported as acute in 87 patients (79.8%); of these reactions, 57.5% were mild and 31% were moderate in severity.
  • There were 10 (11.5%) severe infusion reactions, of which 8 resulted in an emergency room visit.
• The common acute reactions were headache (23%), pruritus (14.9%), dyspnea (13.8%), flushing (13.8%), chest tightness/discomfort (11.5%), and nausea and/or vomiting (10.3%).
• A total of 1.8% of infusion reactions (2/109) occurred with the first infusion and 11% (12/109) with the second infusion.
• At least 1 infusion reaction was reported in 14.3% of patients during induction dosing and in 6.8% of patient during maintenance therapy (P=0.0135).
• Infusion reactions were more common in women than in men (P<0.0001) with a perinfusion incidence of 2.8% in women and 1.1% in men.
• The most common management approaches to acute infusion reactions included infusion pause and restart (32.2% of infusion reactions) and administration of antihistamines (26.4% of infusion reactions).
• In 14 patients, the infusion was stopped and not continued; 5 of these patients were able to complete their next scheduled infusion while 9 patients did not receive any additional infusions.
• Of the patients who experienced an infusion reaction and continued therapy, 69.8% (30/43) did not experience any subsequent reactions.

Bartoli et al (2016)⁵ conducted a retrospective chart review to evaluate the incidence of infusion reactions in patients receiving REMICADE, with and without premedication.

• Clinical charts of patients with RA, PsA, and AS who received REMICADE (5 mg/kg at week 0, 2, and 6, and every 6-8 weeks thereafter) from January 2002 to December 2014 were reviewed.
• Patients were grouped based on the type of premedication:
  • Group 1 (January 2002 to December 2006; n=51): no premedication
  • Group 2 (January 2007 to December 2011; n=35): acetaminophen 500 mg orally, intravenous (IV) esomeprazole 40 mg, IV hydrocortisone 5 mg/kg, and IV chlorpheniramine maleate 10 mg
  • Group 3 (January 2012 to December 2014; n=19): acetaminophen 500 mg orally, hydroxyzine 25 mg orally, IV ranitidine 50 mg, and IV 6-methylprednisolone 100 mg
• Adverse events were recorded during the infusion and in the following hours and weeks (at control visits).
• Infusion reactions were observed in 23 of 51 (45.1%) patients in group 1, in 7 of 35 (20%) patients in group 2, and none of 19 (0%) patients in group 3.
• A total of 25 (83.3%) mild and 5 (16.7%) moderate infusion reactions were observed, while no severe infusion reactions and no anaphylactic reactions occurred.
• The number of infusion reactions to REMICADE was significantly lower in group 2 (P=0.021) and group 3 (P<0.001) compared to group 1.
• The incidence of infusion reactions was significantly lower in group 3 than in group 2 (P<0.043).
• Patients in group 1 had a relative risk of developing an infusion reaction 2.5 times higher than group 2.

Kelsall et al (2012)⁶ conducted a retrospective chart review to evaluate acute and delayed infusion reactions in a cohort of REMICADE patients receiving treatment for inflammatory arthritis.

• Between 2000 and 2008, 376 patients were referred to the Mary Pack Arthritis Centre REMICADE clinic. Two hundred patients were included in the analysis, of which, 135 (67%) had RA, 23 (12%) had PsA, 22 (11%) had AS, 6 (3%) had ocular inflammatory disease, and 14 (7%) had other inflammatory arthritis.
• The mean age for all patients was 50.9±14.6 years and the majority (69%) of patients were women. At the time of the first infusion, the mean disease duration was 15.8±10.9 years.
• A total of 4399 REMICADE infusions were administered for the 200 patients in the cohort. All patients received an average of 22±19 REMICADE infusions (range, 1-74 REMICADE infusions). Patients were followed for a mean of 140±132 weeks.
• The primary outcome of the study was the occurrence of an acute infusion reaction, defined as any AE occurring during infusions or 1-2 hours after each infusion. The secondary outcome was the occurrence of delayed infusion reactions 1-14 days after an infusion.
• Of the 200 patients included in the analysis, 90 (45%) did not experience any acute infusion reactions and 110 (55%) experienced at least 1 acute infusion reaction episode.
• Of the 110 patients who experienced at least 1 acute infusion reaction episode, 31 experienced an acute episode that resulted in an incomplete infusion, with 61.3% of infusion reactions characterized as a moderate in presentation and 25.8% as severe in presentation.
• During follow-up, the number of episodes of acute reactions observed in patients ranged from 1-7 with the greatest proportion of patients (43.6%) experiencing only 1 episode.
• Of the 4399 infusions in all patients, 258 infusions that resulted in an acute reaction were recorded in total for an overall rate of 5.9%.
• Most of the acute infusion reaction episodes were deemed as causally related to the concurrent REMICADE infusion (59.7%), with mild or moderate reactions occurring in 42.6% and 43.8% of patients, respectively.
• There were a total of 508 specific manifestations of acute infusion reactions recorded in all patients. The most commonly affected sites were the head and neck, with acute infusion reactions occurring in 160/508 (31.5%) patients, and the skin, with acute infusion reactions occurring in 107/508 (21.1%) patients.
• Specifically, the most commonly observed reactions were pruritis of the trunk/extremities occurring in 57/508 (11.2%) patients, headache in 49/508 (9.6%) patients, facial flushing in 37/508 (7.3%) patients, and chest tightness in 36/508 (7.1%) patients.

Moss et al (2008)⁷ conducted a retrospective chart review to examine long-term outcomes after initiation of REMICADE therapy in 287 patients with CD.

• Patients completed a median of 6 REMICADE infusions and received a combined total of 2715 infusions.
• A total of 51 (18%) patients developed at least 1 infusion reaction and 162 (6%) infusions were associated with reactions.
• Acute infusion reactions occurred in 61% (31/51) of patients and 39% (20/51) of patients experienced delayed infusion reactions.
  • Reactions were considered mild in 29% (15/51) of cases, moderate in 67% (34/51) of cases, and severe in 4% (2/51) of cases.
  • The most commonly occurring infusion reactions included rash/hives (13/51, 26%) and myalgia/arthralgia (13/51, 26%).
• Factors associated with a higher risk of infusion reactions included ileocolonic disease (OR 2.2 [95% CI, 1.1-4.4], P=0.03) and episodic therapy (OR 2.4 [95% CI, 1.2-4.7], P=0.01).
• The concomitant use of azathioprine (AZA) or 6-mercaptopurine (6-MP) with REMICADE was associated with a reduced risk of infusion reactions (OR 0.4 [95% CI, 0.2-0.8], P=0.007), and in a multivariate analysis, only concomitant use of AZA or 6–MP with REMICADE maintained a significant association with a reduced risk of infusion reactions (OR 0.3 [95% CI, 0.2-0.9], P=0.007).
• Subsequent discontinuation of REMICADE occurred in 30 patients due to AEs.
  • Six patients were reinfused and 3 patients were switched to another anti-tumor necrosis factor (TNF) agent.
• The impact of infusion reactions on outcomes revealed that patients experiencing an infusion reaction while receiving REMICADE had a primary response rate of 71%; similar to that reported in clinical trials.
• Of REMICADE treated patients who experienced an infusion reaction, remission rates were 50%, 33%, and 28% at 1, 2, and 5 years, respectively.
• Patients experiencing infusion reactions had a significantly reduced ratio of primary response (OR 0.4 [95% CI, 0.2-0.9], P=0.03) and remission at 2 years (OR 0.4 [95% CI, 0.2-0.8], P=0.01).

Kolho et al (2007)⁸ conducted a retrospective chart review evaluating severe adverse reactions in pediatric patients (mean age, 14 years) with CD or UC that received REMICADE since 2000 in Helsinki and Tampere University Hospitals.

• A total of 23 pediatric patients (22 with CD, 1 with UC) were identified as receiving a total of 141 REMICADE infusions.
  • In these patients, most REMICADE infusions were initiated at 5 mg/kg, however, 5 patients received doses of 3-4 mg/kg.
• The majority of patients were receiving concomitant medication therapy with AZA or oral glucocorticoids (ie, prednisolone or budesonide) at the start of REMICADE therapy.
• Major adverse reactions occurred in 6 patients (26%), of which, 4 were considered to be acute reactions.
• Minor reactions were reported in 4 patients during the infusion requiring no additional medication therapy.

Zelinger et al (2006)⁹ conducted a retrospective chart review of 451 patients (432 RA, 19 AS) from 9 rheumatology centers.

• Patients completed a median of 20 infusions and a total of 9539 infusions were administered.
• Three hundred and fifty-five patients were receiving concomitant MTX.
• Treatment with REMICADE was continued by 88% and 77% of patients at 24 and 48 months, respectively.
• Approximately 2% (139) of infusions were associated with an infusion reaction, 4 of which were considered serious.
• Among 449 patients for whom data was available, 21% experienced at least 1 infusion reaction (pruritus was most common).
• Five patients discontinued treatment due to an infusion reaction.

Kapetanovic et al (2006)¹⁰ assessed the effect of baseline anti-nuclear antibodies (ANA) and the concomitant administration of MTX on the incidence of infusion-related reactions in patients with RA or other spondylarthropathies (SpA).

• ANA status was evaluated at initiation of treatment with REMICADE in a total of 213 patients with RA and 76 patients with a SpA (AS [n=21], PsA [n=43], inflammatory bowel-related arthritis [n=5], and undifferentiated SpA [n=7]).
• ANA presence at baseline or the administration of REMICADE as monotherapy or without MTX were identified as independent risk factors for infusion reactions in patients with RA.
• The combination of both risk factors increased the risk of developing an infusion reaction. The most pronounced risk of developing an infusion reaction occurred when both ANAs were present at baseline and REMICADE was administered without MTX.
• Patients that were ANA negative at baseline and were given REMICADE + MTX were least likely to experience an infusion reaction.
• There was no correlation between dosage increase over time and the development of an infusion reaction.

Cheifetz et al (2003)¹¹ evaluated the incidence and management of acute infusion reactions to REMICADE in a retrospective study of 165 patients with CD who had received a total of 479 REMICADE infusions.

• Most acute infusion reactions were mild to moderate in severity, with only 1% of infusions being associated with an acute severe reaction.
• The authors concluded that the overall incidence of infusion reactions to REMICADE was low, occurring in 10% of patients or 6% of infusions.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 July 2023.